Institut Curie, PSL Research University, CNRS, UMR144, Biology of Centrosomes and Genetic Instability Laboratory, Paris, France.
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Nature. 2022 Apr;604(7904):146-151. doi: 10.1038/s41586-022-04578-4. Epub 2022 Mar 30.
Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications-doublings of the entire complement of chromosomes-are linked to genetic instability and frequently found in human cancers. It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis; however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis. Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization.
二倍体和稳定的核型与动物的健康和适应性相关。相比之下，全基因组加倍——即染色体全部加倍——与遗传不稳定性相关，并经常在人类癌症中发现。已经证实，全基因组加倍通过异常有丝分裂引发染色体不稳定性；然而，四倍体在第一间期的直接后果尚不清楚。这是一个关键问题，因为诸如胞质分裂失败等单个全基因组加倍事件会促进肿瘤发生。在这里，我们发现人类细胞在诱导四倍体形成后的第一个 S 期的 DNA 复制过程中经历了高频率的 DNA 损伤。通过 DNA 梳理和单细胞测序，我们表明 DNA 复制动力学受到干扰，产生了欠复制和过复制区域。从机制上讲，我们发现这些缺陷是由于 G1/S 转换期间蛋白质短缺导致的，这会损害 DNA 复制的保真度。这项工作表明，在单个间期内，未被调度的四倍体细胞可以获得高度异常的核型。这些发现为四倍体化后有利于肿瘤发生的遗传不稳定景观提供了一种解释。
